Transcriptional regulation of the human FasL promoter-enhancer region.
The human FasL enhancer region was cloned and functionally characterized in transformed and primary T cells. Within the 2.3 kilobase pairs of the FasL untranslated region, the distal 3' 300-base pair portion contains a single transcription initiation site and confers basal and inducible transcriptional activity. Stimuli that increase [Ca2+]i such as CD3 cross-linking or ionomycin, but not activation of protein kinase C, were found to induce FasL enhancer transcription in a cyclosporin-sensitive manner. Moreover, calcineurin and NFAT, but not AP1, were identified as necessary and sufficient effectors in driving FasL transcription through an NFAT cis-acting motif (GGAAA). Additional modes of T cell activation such as CD4 cross-linking were also found to induce NFAT binding to the FasL enhancer region and to functionally transactivate its transcription. These results indicate that the induction of FasL gene transcription in T cells after CD3 or CD4 activation is selectively mediated by calcineurin and NFAT.
Holtz-Heppelmann
C J
CJ
Department of Experimental Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Algeciras
A
A
Badley
A D
AD
Paya
C V
CV
D001483:Base Sequence; D015704:CD4 Antigens / Q000378:metabolism; D019703:Calcineurin / Q000378:metabolism; D003001:Cloning, Molecular; D018076:DNA, Complementary; D004268:DNA-Binding Proteins / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D053222:Fas Ligand Protein; D005786:Gene Expression Regulation; D006801:Humans; D019169:Jurkat Cells; D008562:Membrane Glycoproteins / Q000235:genetics*; D008969:Molecular Sequence Data; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
D015704:CD4 Antigens; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D014157:Transcription Factors; D019703:Calcineurin